New Players in Urethral Closure; Defining the Role of a Novel Long Noncoding RNA

描述（由申请人提供）：尿道下裂（尿道开口的异常位置）是美国最常见的出生缺陷之一，大约每140个活产男婴中就有1个受到影响。尽管发病率很高，但人们对这种常见疾病的病因知之甚少。一些基因已经被分离出来，使阴茎易患尿道下裂。然而，单纯的遗传原因并不能解释1970-1993年美国尿道下裂发病率翻倍的现象。由于不适当的雌激素暴露或雄激素信号抑制都可诱发尿道下裂，其增加归因于环境因素，其中环境内分泌干扰物（eed）是主要候选者。因此，了解激素与调节尿道关闭的关键分子通路之间的相互作用，对于确定尿道下裂的病因和临床治疗的潜在靶点至关重要。在这个提议中，我们将定义一个新的长链非编码RNA分子（lnc353）的功能，这是小鼠尿道关闭所必需的。lnc353的缺失导致尿道关闭完全失败，导致严重的阴囊尿道下裂，反映了人类严重尿道下裂的表型。我们已经表明，lnc353两侧有多个雄激素和雌激素受体反应元件，表明它受激素直接控制，是内分泌干扰的潜在靶点。此外，lnc353在人类基因组的核苷酸水平和物理位置上都是异常高度保守的，这表明它具有重要的发育功能。在这个提议中，我们将定义lnc353在尿道闭合中的功能，它与已知和新的阴茎模式网络的相互作用，它的激素控制和内分泌干扰的潜力。在未来的工作中，我们将确定lnc353的突变是否与人类严重的尿道下裂有关。这项工作将描述一个关键的新球员在正常的尿道关闭和阴茎发育。我们的发现将为这种常见疾病的遗传和激素原因提供急需的信息，并有助于开发诊断和治疗这种疾病的新方法。这些研究在我们评估这种疾病的临床治疗和近几十年来尿道下裂发病率急剧增加的潜在原因之前是基础的。这项研究符合美国国立卫生研究院的使命，特别是通过指导和支持人类疾病的病因、诊断、预防和治疗方面的研究来改善国民的健康；在人类成长和发展的过程中；以及环境污染物的生物效应。

DESCRIPTION (provided by applicant): Hypospadias (the abnormal placement of the urethral opening) is one of the most common birth defects in the USA, affecting approximately 1 in every 140 live male births. Despite its high incidence, relatively little is known about the causes of this common disease. A few genes have been isolated that predispose the penis to hypospadias. However, genetic causes alone cannot explain a doubling in the reported rate of hypospadias in the USA between 1970-1993. Since inappropriate estrogen exposure or inhibition of androgen signaling have both been shown to induce hypospadias, its increase has been attributed to environmental factors, with environmental endocrine disruptors (EEDs) being prime candidates. Thus, understanding the interplay between hormones and the critical molecular pathways regulating urethral closure is essential to define the causes of hypospadias and potential targets for the clinical management of this disease. In this proposal we will define the function of a novel long noncoding RNA molecule (lnc353) that is necessary for urethral closure in mice. Deletion of lnc353 causes a complete failure of urethral closure resulting in a severe penoscrotal hypospadias, mirroring human severe hypospadias phenotypes. We have shown that lnc353 is flanked by multiple androgen and estrogen receptor response elements suggesting it is under direct hormonal control and a potential target of endocrine disruption. Furthermore, lnc353 is unusually highly conserved in the human genome both at the nucleotide level (>80%) and in its physical location, suggesting an important developmental function. In this proposal we will define the function of lnc353 in urethral closure, its interaction with know and novel penile patterning networks, its hormonal control and potential for endocrine disruption. In future work, we will determine if mutations in lnc353 are associated with severe hypospadias in humans. This work will characterize a critical new player in normal urethral closure and penile development. Our findings will provide much needed information on the genetic and hormonal causes of this common disease and aid in the development of new ways to diagnose and treat this condition. Such studies are fundamental before we can assess clinical management of this disease and the potential reasons for the dramatic increase in hypospadias incidence over recent decades. This research is inline with the missions of the NIH, specifically by Improving the health of the Nation by conducting and supporting research in the causes, diagnosis, prevention, and cure of human diseases; in the processes of human growth and development; and in the biological effects of environmental contaminants. PUBLIC HEALTH RELEVANCE: Hypospadias (the abnormal placement of the urethral opening on the penis) is one of the most common birth defects in the USA, affecting approximately 1 in every 140 live male births. Inappropriate exposure to hormones during development has been shown to cause hypospadias and an increase in environmental endocrine disrupting chemicals has been implicated in the doubling in incidence of this disease in the USA between 1970-1993. In this proposal, we will investigate the role of a new long noncoding RNA gene that is necessary for urethral closure and has the potential for hormonal disruption suggesting it could be cause of human sporadic hypospadias.